S. Mathonet on behalf of EBE
CASSS CMC Strategy Forum – EBE satellite session – Sorrento – May 5, 2014
Industry Perspectives on Visible
Particle Requirements and Practices
– An overview of EBE position paper
Primary goal of the EBE position paper
• Problem statement: An acceptance criterion of ‘no’ or ‘free from’ or
“without” visible particles is recognised as totally unrealistic
• Define and justify « Practically Free from Visible Particles » as
acceptance criteria for products effectively free of visible particles
for biotech products (focus on recombinant antibodies)
• As exception, define and justify acceptance criteria for products
containing low level of protein particles
• Provide an insight into current industry practices and reach
consensus on minimum requirements and best practices for visual
inspection
2
EBE position paper layout
3
Position Paper Layout
1. Problem statement
2. Visual Inspection at end of DP manufacturing
3. QC sample testing
a. Release testing including discussion
on sampling plan and size
b. Stability testing including discussion
on sampling plan and size
c. Acceptance criteria and justification
Drug Products effectively free from particle
Drug Products containing low level of proteinaceous particles
4. Proteinaceous particle characterization
5. Patient safety
6. Continuous Process optimization and
Conclusion
Annexes
Inspector certification
Risk assessment and ranking of particle defects
Sampling Plans
Literature references
• Focus of the presentation:
Defining Practically Free from Visible
Particles - Guiding Principles
4
Pharmaceutical development
Commercial formulation and process design
• Fulfilling multiple TPP goals in formulation design may
represent a challenge in achieving a formulation devoid of
protein particles
- e.g. sub-cutaneous liquid formulation with high concentration protein
solutions
pH, osmolality, viscosity, soluble aggregates, opalescence, coloration and
sub-visible/visible particles, syringeability / Injectability when TPP includes
delivery device
• It was however agreed in the EBE Visible Particle Sub-Group
discussion that visual appearance including visible particle
free formulation was a main objective for formulation design
• Evaluation of process holding times and processing conditions that
may bring stress to the protein including formation of protein
particles should be considered in process design
5
6
Visual Inspection process
Fillling into container
100% Visual Inspection
Rejected Part of the batch
AQL Visual Inspection (statistical sampling)
Accepted Part
Pass
QC release Visual Inspection Small sample subset (leverage AQL results when justified)
Fail (1)
Visual Re- (3) Inspection 100% of accepted part
Batch rejection
Rejected Part of the batch
Number of repeat to be justified in Quality System
Batch release
QC Stability Visual Inspection Small sample subset
Investigation Mode/ Re-inspection
Batch rejection
Fail (2)
(1) Rare random occurrence of single source particle
(2) Obvious particle reflective of systemic failure
Pass
Non conformance investigations
Rejected Part of the batch
Periodic Trending of Visual Inspection data (Reevaluate what’s Normal and limits)
(3) As per company-specific QA procedures
100 % visual Inspection
• 100 % inspection is a unit operation after filling. It can be manual, semi-
automated or fully automated.
• Every filled units (100%) are visually inspected for critical, major and minor
defects including particles
• In 100% inspection, for products practically free of visible particles,
any unit with visible particle defect irrespective of its nature is
discarded. It applies to liquid and lyophilisate
• For liquid formulations, protein particles are typically sorted during
100% inspection not being differentiated from other particles
• Visible Particle Defect rate ((i.e. maximum visual defects in % of whole
batch filled) criteria should be in place as representative of the
commercial process
7
100 % visual Inspection
• Inspection conditions defined in EP (and USP draft) monographs are:- 2,000-
3,750 lux- Black and white backgrounds- 5 sec viewing against each
background. The threshold of “visibility” depends on many parameters
and can range from ca. 50 to 400 μm, with different detection probability
• Detection of visible particles is a statistical process, in daily practice,
the detection limit very much depends on:
- Individual operator,
- Inspection system and Inspection time
- Morphology, number and refractive index of the particles, rheology and
opalescence of the solutions as well as other factors.
• Companies may use other, non-EP methods to improve the sensitivity or
ergonomics of the process i.e. use of aids such as magnifying glasses or
differences in lighting conditions or observation times and swirling procedures.
• These conditions may have a pronounced effect on reject rates.
8
AQL Inspection
• AQL testing is done to confirm the quality of the product and to confirm the
efficiency of the 100% visual inspection to remove defective product.
• Inspectors should be independent from those that did the initial inspection
• Particle in solutions are at least a major defect in most companies.
Lowest Acceptable Quality Level applied across companies is 0.65%. If
AQL is exceeded, 100 % inspection may be repeated as per company specific
QA procedures
• Occasional random occurrence is an important concept for visible particle
defect.
- A batch may be passed if within the AQL criteria
- Any AQL failure may generate 100% re-inspection of the accepted part of the
batch and a repeat of AQL testing.
• Companies should define and justify number of repeat in their own quality
systems (usually not more than 2 cycles of re-inspection)
9
AQL Inspection
• Manufacturers are expected to have calculated the capability of
the commercial fill / finish process and use this capability to set
alert / action limits for the whole defect rate compared to filled
units (batch size)
- When these alerts limits show special cause for variation in the process,
additional AQL samples may be required to provide additional
assurance of quality
• Any obvious visible defect issues with regards to nature of
particles and representing a systemic failure (insect wing, rust,
paint, hairs,…) will lead to an investigation/re-inspection
- The investigation should evaluate aseptic processing conditions and
potential for sterility breach, systematic failure may lead to batch reject
10
QC Release Testing
• Option 1: Leverage AQL testing (Real Time Release Testing)
- QC Batch Release testing may take the AQL testing results into account
and can determine the AQL result as sufficient and appropriate to confirm
the specification of ‘practically free from visible particles’
e.g. for iv/sc liquid formulations in vials or prefilled syringes
- This approach requires that the AQL inspectors are trained to the same
level as QC and/or Manufacturing inspectors
- The competent authorities (GMP Inspectorate) may allow the AQL
testing as a release test, within scope of inspection during MAA or variation
review, as required
- Furthermore, by describing the RTRT approach on the drug product
specification, a product manufactured in a non-EU country without MRA
may have ‘relief’ from repeat testing on importation into the EU ?
11
QC Release Testing
• Option 2 Separate QC testing
- Especially if destructive method is involved such as reconstitution
of a lyophilised powder, sample size considerations need to take
this fact into account
QC testing of a small subset of the batch (e.g. 20 units / justified
sample size) and acceptance criteria based on processing
capability and packaging component is sufficient
Reconstitution procedure should be carefully designed
- When visual inspection is required as part of QC testing for
liquid formulations, similar sample size considerations apply
as for lyophilisates
- When the integrity of the sample is not impacted by the testing
(non destructive), reuse of sample for other testing is
acceptable as long as the sample handling and testing conditions
are shown not to effect the product quality
12
QC Release Testing (prefilled pen injectors)
• PFS may be inspected for visible particles, prior to assembly, if
container integrity during assembly is warranted, since
- the pre-filled primary container for the biologics cannot be easily
removed: e.g. the device assembly components lock the PFS inside
- the inspection window in a device might not always be fully adequate
for a visual inspection of particle and cannot be qualified for this use
- disassembly may impact the container closure integrity and create
other cosmetic defects such as scratching that could impair visual
inspection
• Similar proposal is recommended for other assembled biologics/
device combination products
13
QC Stability Testing
• Different practices across companies
- For Practically free from visible particles, it is acceptable to test a sub-
set of samples (justified sample size) using EP / USP draft monographs
visual inspection method and acceptance criteria justified based on
product history (with e.g. random occurrence of single source particle)
- Some companies do not specify Visible Particle in shelf life specification but
visible particles are still monitored in stability storage with a semi-
quantitative assay
E.g. based against a set of standard vials containing defined level of particle
defect with different number of particles – presence of visible particles yes/no
plus particle count)
- FlowImaging replacement on visual inspection - hot debate!
Sensitivity (instrument based versus eye)
Influence of instrument setting/sample handling
Precision
Characterization or QC tool ?
14
QC Stability Testing
• Same stability samples (for non-destructive testing of a liquid
product) may be used for all time-points tested or separate units are
inspected per timepoint
• Using the same stability samples provide an advantage being
able to monitor a possible increase / appearance of particles
over stability e.g. stemming from interactions of formulation and
primary packaging, protein particles etc.
• However, it must be confirmed that the inspection procedures
and related handling (e.g. temperature differences) do not
impact visual inspection results
• More discussion needed on stability testing in EBE Visible Particle
Topic Group!
15
Particle Characterization during product
development or non-conformance investigations
• Identification of the origin of the particle(s), from the environment,
product, packaging components or process is required to support risk
management in control strategy and drive CAPA
• The identification of the whole particle population in a unit or even all
units present challenges
• Limited sample size (e.g., thickness, size, mass of a particle and/or number
of particles), changes to the chemical signature (e.g., by heat impact during
manufacture) and the destructive nature of certain analytical techniques
(“one shot on at the goal”) add to the challenge of particle identification
- A key challenge is isolation of particles, especially single particle around 150
micron. Some inherent protein particles are fragile to filtration and may permeate
the filter or even return back into solution.
• No agreement in the EBE Visible Particle Topic group yet on inherent,
intrinsic, extrinsic particle categorization
16
Particle Characterization during product
development or non-conformance investigations
• A toolset of various (complementary) analytical techniques provides
the best opportunity to characterize particles, particularly protein
particles (Microscopic techniques, Mass spectrometry, FTIR,
Raman spectroscopy, SEM-EDX)
• The identification of visible particles is suggested to be
focused on individual investigations and not be considered for
routine or QC testing
- companies have succeeded however in setting a specification allowing
some level of protein particles that have been characterized and
assessed during clinical trials
Will be addressed in case studies
17
Conclusion: Justification of « practically free »
acceptance criteria in Clinical/Commercial filings
• A suitable justification for the practically free from particles could
include a definition on the intent of the specification and a brief
outline of the manufacturing controls in place to control for visible
particles including the 100% inspection and AQL to ANSI/ASQ Z1.4
or ISO 2859-1 , equivalent standards or better testing
• A holistic approach to control might be taken from raw materials
through to finished product
• When particles detected under the practically free from particles
specification, trigger a non-conformance process, the level of non-
conformance and investigation route would depend on the
assessment of the particle (nature and frequency of occurrence).
• The product history for detection, identification and characterisation
of visible particles should be documented
18
Acknowledgements
• Thanks to all EBE Visible Particle Topic group contributors
- Sharon Adderley, Manufacturing Science and Technology,
Analytical Science, Pfizer
- Patricia W. Cash, Analytical Biotechnology, MedImmune
- Stefan Esswein, NBE Analytical R&D, Abbvie
- Christof Finkler, Analytical Development & Quality Control,
Pharma Technical Development Biologics EU, F.Hoffmann-La
Roche Ltd, Basel, Switzerland
- Andrew Lennard, Regional Regulatory Affairs CMC, Amgen
- Georg Kallmeyer & Hanns-Christian Mahler, Pharmaceutical
Development&Supplies, Pharma Technical Development Biologics
EU, F.Hoffmann-La Roche Ltd, Basel, Switzerland
- Maryam Mazaheri, Analytical Biotechnology , Medimmune
- Klaus Wuchner, PDMS Analytical Development, Janssen R&D
19
Inspector Certification
• Effective inspector selection, training, and monitoring necessary
for a reliable and consistent visual inspection program
- Certification of visual acuity and technical expertise that includes the
ability to detect particulates in test panels
• An inspector must be able to detect a predefined amount of defects
(without detecting a maximum amount of “false positives”) in order to
be qualified. Inspector must be re-qualified in regular intervals
• Ideally, the same principle of training and monitoring shall be
applicable to all personnel performing visual inspection for
visible particles be it during manufacture as part of 100% manual
inspection, AQL testing, QC release and stability testing, QA
reserves/retention and product complaints
• Different company practice- This Annex still heavily discussed in the
EBE Visible Particle Topic Group !
21
Inspector Certification
• Training Process for Inspector
- Introduction to general visual inspection method
Different company practices
- If a defect (incl. particle) library is available a demo of typical defects should be
performed
- Demo of visual inspection method by trainer
- Demo of sample handling and handling (e.g. agitation) method, according to
predefined SOP
- Introduction to defect categories as per predefined SOP
- Proficiency runs using appropriate test panels (qualification defect test set) for
the process and product, as many as required
- Independent Performance runs with defined acceptance criterion level
for particle defects Company specific
22
Inspector Certification
• Maintenance and Monitoring of Visual Inspector
- A minimum of procedure review and assessment in regular intervals .
- A minimum of annual inspector assessment ; compliance to SOP and
ability to detect defects
- Eye exams must be performed in regular intervals
- Inspector must be re-qualified at regular intervals to be considered a
qualified visual inspector. •
23